3-ketoacyl-CoA thiolase, mitochondrial (EC 2.3.1.16) (Acetyl-CoA acetyltransferase) (EC 2.3.1.9) (Acetyl-CoA acyltransferase) (Acyl-CoA hydrolase, mitochondrial) (EC 3.1.2.-) (EC 3.1.2.1) (EC 3.1.2.2) (Beta-ketothiolase) (Mitochondrial 3-oxoacyl-CoA thiolase) (T1)

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p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria.

Although the p46Shc isoform has been known to be mitochondrially localized for 11 years, its function in mitochondria has been a mystery. We confirmed p46Shc to be mitochondrially localized and showed that the major mitochondrial partner of p46Shc is the lipid oxidation enzyme 3-ketoacylCoA thiolase ACAA2, to which p46Shc binds directly and with a strong affinity. Increasing p46Shc expression inhibits, and decreasing p46Shc stimulates enzymatic activity of thiolase in vitro Thus, we suggest p46Shc to be a negative mitochondrial thiolase activity regulator, and reduction of p46Shc expression activates thiolase. This is the first demonstration of a protein that directly binds and controls thiolase activity. Thiolase was thought previously only to be regulated by metabolite balance and steady-state flux control. Thiolase is the last enzyme of the mitochondrial fatty acid beta-oxidation spiral, and thus is important for energy metabolism. Mice with reduction of p46Shc are lean, resist obesity, have higher lipid oxidation capacity, and increased thiolase activity. The thiolase-p46Shc connection shown here in vitro and in organello may be an important underlying mechanism explaining the metabolic phenotype of Shc-depleted mice in vivo.

MeSH Terms

  • Acetyl-CoA C-Acyltransferase
  • Animals
  • Binding, Competitive
  • Blotting, Western
  • Cell Line
  • Energy Metabolism
  • Fatty Acids
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lipid Metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria
  • Mitochondrial Proteins
  • NIH 3T3 Cells
  • Oxidation-Reduction
  • Protein Binding
  • Protein Isoforms
  • RNA Interference
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1

Keywords

  • Shc
  • aging
  • diet
  • high fat diet resistance
  • insulin
  • lipid metabolism
  • longevity
  • mitochondria
  • p46Shc
  • thiolase